Phenoxyphenylamino acids



United States Patent 3,520,922 PHENOXYPHENYLAMINO ACIDS Hans A. Wagner, Skokie, IlL, assignor to G. D. Searle & Co., Chicago, Ill., a corporation of Delaware No Drawing. Filed Sept. 7, 1967, Ser. No. 665,993

procedure is a modification of one described by Winter et al., Proc. Soc. Exper. Biol. and Med., 111, 544 (1962). Compound is administered subcutaneously or intragastrically, dissolved or suspended in 0.5 ml. of aqueous 0.86 sodium chloride, propylene glycol, a mixture of these lint. Cl. C07c 101/72 5 vehicles, or corn oil, to each of male rats weighing US. Cl. 260-519 7 Claims 100-130 gm. A like group of rats to which is identically and concurrently administered vehicle alone serves as controls. Precisely 1 hr. later, each animal is in'ected under ABSTRACT OF THE DISCLOSURE 10 the plantar surface of each hind foot with Oil ml. of an Preparation f th ti d compounds, h as N- aqueous 1% solution of carrageenin (Marine Colloids, (p-phenoxyphenynglycine d N- i h Inc., Type 402). A compound is considered anti-inflamphenynglycine, d h i l bl h l i l propmatory if the average total circumference (T) of the hind erties, including anti-microbial and anti-inflammatory acfeet 111 the gfOllP treated therewith. Which is asured in ti i i are di l d arbitrary units 5 hr. after the carrageenin injection, is significantly (P5005) less than the corresponding value (C) for the control group. Results of the testing of the This invention relates to phenoxyphenylamino id products of Examples 1 and 2 hereinafter by this proceand processes for the preparation thereof. More particudure are shown in Table I.

TABLE I Dose,

mg. Route 0 T 0-0. Conclusion Product:

x.1 5 Oral 102.0 98.6 3.4 Anti inflammatory. EX.2 Subcut. 103.2 98.1 5.1 Do.

larly, this invention provides new, useful, and unobvious Those skilled in the art will recognize that observations chemical compounds of the formula of activity in standardized tests for particular pharma- X cological effects as hereinbefore set forth are fundamental l to the development of valuable new drug products, both Q F OH veterinary and human.

Q0 R Preparation of the compounds of this invention proceeds by heating an appropriate phenoxyaniline wherein X represents hydrogen or a nitroso'radical and R represents hydrogen or an alkyl or phenyl radical. g @Nllz Among the alkyl radicals represented by R, lower alkyl 30 Q groupings are preferred, i.e., methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, neopentyl, and whale carboxylic acid hexyl, isohexyl, heptyl, and like monovalent, saturated, h1 CHCOOH acyclic straightor branched-chain, hydrocarbon radicals 40 a I of empirical formula R C,,H (hal representing chlorine or bromine and R being dewherein n represents a positive integer less than 8. Alfined as before) In an Inert alkahne Solvent 4 f though the phenoXy constituents of the instant compounds Such as aqlleous ethanffl or z-methoxfithanm coniammg can, for the purposes of this invention, be in any of the 636655 sodmm hydr9X1de methoxlde, to positions ortho, meta, and para to the nitrogen atom as gwe the Correspondmg ammo acld shown in the introductory formula, the para position is NHOHOOOH the position of choice. I

The compounds to which this invention relates' are Go R useful by reason of their valuable pharmacological properties. Thus, for example, they inhibit the growth of g defined as before) The latief Compound, 511$- bacterica such as Diplococcus pneumoniae, protozoa such pended 111 Water -'P Y- in y as T etrahymena gelleii, and fungi such as Trichophyton chloric acid, afiolds the o r sp nding nitroso commentagrophytes; and they are anti-infammatory agents. P= f hereqf 011 Contact Wlfih all aqueous S0111t1011 of In addition, the nitroso compounds hereof inhibit the SOdlum r te growth of the fungus, Candida dlbicans, and algae such The fellowmg examples describe in detail compounds as Chlorella vulgaris. illustrative of the present invention and methods which Th anti-inflammatory activity of th in t nt have been devised for their preparation. However, the pounds is evident from the results of a standardized test in i n i n to be construed as limited y, either for their capacity to diminish or prevent the edema in- 0 in spirit or in scope, since it will be apparent to those duced in rats by injection of carrageenin. The rationale for this test is that formation of local edema is a characteristic manifestation of inflammation which can be counteracted by known anti-inflammatory agents. The

skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth,

3 temperatures are given in degrees centigrade and relative amounts of materials in parts by Weight, except as otherwise noted.

Example 1.N- (phenoxyphenyl) glycine To a solution of 92 parts of p-phenoxyaniline in 500 parts of ethanol is added 47 parts of chloroacetic acid, followed by a solution of 20 parts of sodium hydroxide in 500 parts of water. The resultant mixture is heated at the boiling point under reflux with stirring for 12 hours during which solution occurs. it is then poured into 2000 parts of water. The crystalline solid which forms is filtered off and taken up in a solution of 75 parts of sodium hydroxide in 1500 parts of water. The resultant solution is filtered, washed with ether, and then acidified with 250 parts of acetic acid. The solid thus obtained is filtered off, washed with water, dried in air, and recrystallized from ether to give N-(p-p-henoxyphenyl) glycine melting at 110112. The product has the formula Example 2.N-nitroso-N- (p-phenoxyphenyl) glycine Example 3 .N- (p-phenoxyphenyl) alanine Substitution of 76 parts of 2-bromopropionic acid, 400 parts of ethanol, and 400 parts of water for the 47 parts of chloroacetic acid, 500 parts of ethanol, and 500 parts of Water, respectively, called for in Example 1 affords,

by the procedure there detailed, N-(p-phenoxyphenyl) alanine melting at approximately 151452". The product has the formula Example 4.-N-nitroso-N- (p-phenoxyphenyl alanine To a solution of 70 parts of N-(p-phenoxyphenyl) alanine in 500 parts of 5% hydrochloric acid at 5 is slowly added, during 20 minutes, a solution of 25 parts of sodium nitrite in 40 parts of water. After 1 hr., a crystalline precipitate is thrown down which, filtered ofi, washed with water, dried in air, and recrystallized from a mixture of ether and n-pentane, affords N-nitroso-N- (p-phenoxyphenyDalanine melting at approximately 89- 90". The product has the formula IIIO Example 5 .--N- p-phenoxyphenyl valine A solution of 1 48 parts of p-phenoxyaniline and 72 parts of Z-bromoisovaleric acid in 400 parts of 2-methoxyethanol (Methylcellosolve) is heated at the boiling point under reflux with agitation for 18 hr., whereupon 40 parts mula Example 6.o;-Pentyl-N- (p-phenoxyphenyl) glycine Substitution of 83 parts of 2-bromoheptanoic acid for the Z-bromoisovaleric acid called for in Example 5 affords, by the procedure there detailed, a-pentyl-N-(pphenoxyphenyl) glycine, having the formula Example 7 .a-Heptyl-N- (p-phenoxyphenyl glycine Substitution of 94 parts of 2-bromononanoic acid for the 2-bromoisovaleric called for in Example 5 affords, by the procedure there detailed, a-heptyl-N-(p-phenoxyphenyl) glycine. The product has the formula Example 8 .N- (p-phenoxyphenyl -a-phenylglycine A mixture of 172 parts of p-phenoxyaniline, 200- parts of a-bromophenylacetic acid, .51 parts of sodium methoxide, and 1000 parts of 2-methoxyethanol is heated at the boiling point under reflux with agitation for 8 hr. Approximatly 40 parts of sodium hydroxide is thereupon introduced and the resultant mixture steam-distilled to remove solvent. The distilland is cooled and washed well with dichloromethane and ether, then acidified with parts of acetic acid. The mixture thus obtained is stirred while a solid precipitates, which is filtered off, washed with water, dried in air, and recrystallized from acetone to give N-(p-phenoxyphenyl)-a-phenylglycine melting at 1-68170. The product has the formula What is claimed is: 1. A compound of the formula wherein X represents hydrogen or nitroso and R represents hydrogen, lower alkyl, or phenyl.

2. A compound according to claim 1 which is N-(pphenoxyphenyl) glycine.

3. A compound according to claim 1 which is N- nitroso-N- (p-phenoxyphenyl glycine.

4. A compound according to claim 1 wherein R represents lower alkyl.

5. A compound according to claim 1 which is N-(pphenoxyphenyl) alanine.

6. A compound according to claim 1 which is N- nitroso-N- (p-phenoxyphenyl) alanine.

6 7. A compound according to claim 1 which is N-(p; LORRAINE A. WEINBERGER, Primary Examiner phenoxyphenyl)'a'phenylglycmc' L. A. THAXTON, Assistant Examiner References Cited U S Cl XR UNITED STATES PATENTS 5 424319 3,410,891 11/1968 Hughes et a1 260519 

